Muscle atrophy is known to occur in paravertebral muscles, lower-limb soleus muscles, and such following exposure to a space environment which is a microgravity environment, a long-term bedrest, or a plaster cast-immobilized state. Damage and necrosis of skeletal muscles are compensated by regeneration, and when muscle regeneration does not fully compensate for the necrosis of muscle fibers, muscle atrophy is thought to occur. It is known that in the regeneration process following skeletal muscle damage, satellite cells are recruited. Satellite cells are tissue-specific stem cells normally existing as a quiescent (inactive) state in skeletal muscles. They proliferate and differentiate, and fuse with muscle fibers to promote muscle regeneration. However, the factors that promote satellite cell recruitment, growth, and differentiation in vivo have not been clarified yet.
IL-6 is a cytokine called B-cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor involved in the activation of B-cell lymphocytes (Non-patent Document 1), and was later revealed to be a multifunctional cytokine that influences the function of various cells (Non-patent Document 2). IL-6 has been reported to induce maturation of T lymphocyte cells (Non-patent Document 3).
IL-6 transmits its biological activity via two kinds of proteins on the cell. One of the proteins is the IL-6 receptor which is a ligand binding protein to which IL-6 binds and has a molecular weight of about 80 kDa (Non-patent Document 4; and Non-patent Document 5). In addition to a membrane-bound form that penetrates and is expressed on the cell membrane, the IL-6 receptor is also present as a soluble IL-6 receptor which mainly consists of the extracellular region of the membrane-bound form.
The other is the membrane protein gp130 which has a molecular weight of about 130 kDa and is involved in non-ligand binding signal transduction. The biological activity of IL-6 is transmitted into the cell through formation of the IL-6/IL-6 receptor complex by IL-6 and IL-6 receptor and binding of the complex with gp130 thereafter (Non-patent Document 6).
IL-6 inhibitors are substances that inhibit the transmission of IL-6 biological activity. Until now, antibodies against IL-6 (anti-IL-6 antibodies), antibodies against IL-6 receptors (anti-IL-6 receptor antibodies), antibodies against gp130 (anti-gp130 antibodies), IL-6 variants, partial peptides of IL-6 or IL-6 receptors, and such have been known.
There are several reports regarding the anti-IL-6 receptor antibodies (Non-patent Document 7; Non-patent Document 8; Patent Document 1; Patent Document 2; and Patent Document 3). A humanized PM-1 antibody, which had been obtained by transplanting into a human antibody, the complementarity determining region (CDR) of mouse antibody PM-1 (Non-patent Document 9), which is one of anti-IL-6 receptor antibodies, is known (Patent Document 4).
To date, insulin-like growth factor-I (Non-patent Document 10) and anti-myostatin antibodies (Non-patent Document 11) have been known to suppress muscle atrophy and promote muscle regeneration. However, it is not clear whether cytokines, such as IL-6, influence muscle regeneration or not.
Documents of related prior arts for the present invention are described below.    [Patent Document 1] International Patent Application Publication No. WO 95/09873.    [Patent Document 2] French Patent Application No. FR 2694767.    [Patent Document 3] U.S. Pat. No. 5,216,128.    [Patent Document 4] WO 92/19759.    [Non-patent Document 1] Hirano, T. et al., Nature (1986) 324, 73-76.    [Non-patent Document 2] Akira, S. et al., Adv. in Immunology (1993) 54, 1-78.    [Non-patent Document 3] Lotz, M. et al., J. Exp. Med. (1988) 167, 1253-1258.    [Non-patent Document 4] Taga, T. et al., J. Exp. Med. (1987) 166, 967-981.    [Non-patent Document 5] Yamasaki, K. et al., Science (1988) 241, 825-828.    [Non-patent Document 6] Taga, T. et al., Cell (1989) 58, 573-581.    [Non-patent Document 7] Novick, D. et al., Hybridoma (1991) 10, 137-146.    [Non-patent Document 8] Huang, Y. W. et al., Hybridoma (1993) 12, 621-630.    [Non-patent Document 9] Hirata, Y et al., J. Immunol. (1989) 143, 2900-2906.    [Non-patent Document 10] Barton-Davis, E. R. et al., Proc. Natl. Acad. Sci. USA (1998) 95, 15603-15607.    [Non-patent Document 11] Bogdanovich, S. et al, Nature (2002) 420, 418-421.    [Non-patent Document 12] Dangott B. et al., Int J. Sports Med. (2000) 21, 13-16.    [Non-patent Document 13] Darr K C. and Schultz E., J. Appl. Physiol. (1989) 67, 1827-1834.    [Non-patent Document 14] Garry D J. et al., PNAS (2000) 97, 5416-5421.    [Non-patent Document 15] Garry D J. et al., Dev. Biol. (1997) 188, 280-294.    [Non-patent Document 16] Jejurikar S S. et al., Plast Reconstr Surg (2002) 110, 160-168.    [Non-patent Document 17] Mauro A., J. Biochem Cytol. (1961) 9, 493-498.    [Non-patent Document 18] McCormick K M and Schultz E., Dev. Dyn. (1994) 199, 52-63.    [Non-patent Document 19] Moss F P. and Leblond C P., Anat. Rec. (1971) 170, 421-435.    [Non-patent Document 20] Mozdziak P E. et al., Biotech. Histochem. (1994) 69, 249-252.    [Non-patent Document 21] Mozdziak P E. et al., J. Appl. Physiol. (2000) 88, 158-164.    [Non-patent Document 22] Mozdziak P E. et al., J. Appl. Physiol. (2001) 91, 183-190.    [Non-patent Document 23] Mozdziak P E. et al., Eur. J. Appl. Physiol. Occup. Physiol. (1998) 78, 136-40.    [Non-patent Document 24] Schultz E., Dev. Biol. (1996) 175, 84-94.    [Non-patent Document 25] Schultz E. et al., J. Appl. Physiol. (1994) 76, 266-270.    [Non-patent Document 26] Schultz E. et al., Muscle Nerve. (1985) 8, 217-222.    [Non-patent Document 27] Snow M H., Anat. Rec. (1977) 188, 181-199.    [Non-patent Document 28] Snow M H., Anat. Rec. (1990) 227, 437-446.    [Non-patent Document 29] Wang X D., Am. J. Physiol. Cell Physiol. (2006) 290, C981-C989.